PL202044B1 - Novel biarylcarboxamides - Google Patents

Abstract

A compound of formula (I), wherein A represents (II), (III), (IV) or (V), D represents oxygen or sulfur; E represents a single bond, oxygen, sulfur, or NR<10>; R represents hydrogen or methyl; Ar<1> represents a 5- or 6-membered aromatic or heteroaromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom; Ar<2> represents a 5- or 6-membered aromatic or heteroaromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom or; an 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system containing zero to three nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom; the aromatic rings Ar<1> and Ar<2> are optionally substituted with one or three substituents selected from: halogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, CN, NO2, NR<1>R<2>, CH2NR<1>R<2>, OR<3>, CH2OR<3>, CO2R<4>, CF3; R<1>, R<2> and R<3> are independently C1-4alkyl, aryl, heteroaryl, C(O)R<5>, C(O)NHR<6>, C(O)R<7>, SO2R<8> or R<1> and R<2> may together be (CH2)jG(CH2)k where G is oxygen, sulfur, NR<9>, or a bond; j is 2 to 4; k is 0 to 2; R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, and R<10> are independently C1-4alkyl, aryl, or heteroaryl; or an enantiomer thereof and pharmaceutically acceptable salts thereof; with the provisos that: (1) if D represents oxygen, E represents a single bond, and A represents (II) and either Ar<1> or Ar<2> represents a pyrazole ring, then all optional substituents on the pyrazole ring shall be hydrogen; and (2) if Ar<1> represents a pyridine ring, Ar<2> represents an aryl ring, and A represents (II), then all optional substituents on the pyridine ring shall be hydrogen; and (3) formula (I) does not represent (a); processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment or prophylaxis of psychotic and intellectual impairment disorders.

Description

Description of the invention

The present invention relates to novel biaryl carboxamides, their use, a process for the preparation of biaryl carboxamides and the intermediates used in this process.

McDonald et al. (1995), in "Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology", Chapter 5, in Annual Reports in Medicinal Chemistry, Vol. 30, pp. 41-50, Academic Press Inc., San Diego, CA ; and Williams et al. (1994), in "Neuronal Nicotinic Acetylcholine Receptors", Drug News & Perspectives, Vol. 7, pp. 205-223 describe the use of compounds that bind to nicotinic cholinergic receptors in the treatment of many disorders caused by decreased cholinergic activity. such as Alzheimer's disease, cognitive impairment or attention deficit disorder, anxiety, depression, smoking cessation, in neurological protection, schizophrenia, analgesia, Tourette's syndrome and Parkinson's disease.

There was a need to provide active substances that are strong ligands for nicotinic cholinergic receptors (nAChRs).

The invention relates to biaryl carboxamides of the general formula I:

D where:

A means:

E is a single bond, oxygen, sulfur or NR ¹⁰ ;

R is hydrogen or methyl;

Ar ¹ is a benzene, furan, thiophene or thiazole ring;

Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl;

Ar ¹ and Ar ² are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO 2, NR ¹ R ^2, CH 2 NR ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3; but when Ar ¹ is a benzene ring and Ar ² is quinolinyl then Ar ² is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ^2, CH 2 NR ¹ R ^2, OR ^3, CH 2 OR ³ and CO 2 R ^4;

R ¹ , R ² and R ³ are independently C 1 -C 4 -alkyl, C (O) R ⁵ , C (O) NHR ⁶ , C (O) R ⁷ , SO ² R 8, or R ¹ and R ² together can be ( CH2) JG (CH2)] k where G is oxygen, sulfur, NR ⁹ or a single bond;

j is 2, 3 or 4; k is 0, 1 or 2;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently C ₁ -C ₄ alkyl; or their enantiomers and their pharmaceutically acceptable salts, except that formula I does not represent:

PL 202 044 B1

Preferred compounds of the invention are compounds of formula I in which D is oxygen.

Compounds of formula I in which E is a single bond are preferred.

Also preferred are compounds of formula I, wherein E is oxygen or NR ¹⁰ .

Preferred compounds of the invention are compounds of formula I in which A is

₂

Compounds of formula I are preferred, wherein Ar ² is phenyl, furyl, thiophenyl or pyridyl.

Preferred compounds of the invention are compounds of formula I in which Ar ¹ is substituted exclusively with the carboxamide group or the C (= D) NHA thiocarboxamide group.

Compounds of formula I in which -EAr ² and the carboxamide or thiocarboxamide group C (= D) NHA, the substituents on the Ar ¹ ring, are in the 1.3 position with respect to each other are preferred.

Preferred are compounds of formula I wherein Ar ¹ or Ar ² is optionally substituted with a substituent selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO 2, NR ¹ R ² , CH2NR ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3.

Preferred compounds according to the invention are compounds of formula I in which:

A means:

D is oxygen;

E is a single bond;

Ar ¹ is a benzene, furan, thiophene or thiazole ring;

Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl;

the aromatic ring of Ar ¹ is substituted with only Ar ² and a carboxamide group, C (= O) NHA;

Ar ² is optionally substituted with a substituent selected from halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ^2, CH 2 NR ¹ R ^2, OR ^3, CH 2 OR ^3, CO 2 R ⁴ and CF3. Compounds of formula I in which Ar ¹ is a benzene, furan or thiophene ring, or enantiomers thereof and pharmaceutically acceptable salts thereof, are preferred.

Preferred compounds according to the invention are compounds of formula I in which:

A means:

D is oxygen;

E is oxygen or NH;

Ar ¹ is a benzene, furan, thiophene or thiazole ring;

Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl;

the aromatic ring Ar ¹ is substituted solely with EAr ² and the group C (= O) NHA;

Ar ² is optionally substituted with a substituent selected from halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ^2, CH 2 NR ¹ R ^2, OR ^3, CH 2 OR ^3, CO 2 R ⁴ and CF3.

PL 202 044 B1

Compounds of formula I in which Ar ¹ is a benzene, furan or thiophene ring, or enantiomers thereof and pharmaceutically acceptable salts thereof, are preferred.

Compounds of formula I in which EAr ² and the carboxamide group, C (= O) NHA, on the Ar ¹ ring are in the 1.3 position with respect to each other, or the enantiomer thereof and pharmaceutically acceptable salts thereof, are preferred.

The preferred compounds of the invention include the following compounds:

N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-pyridyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methoxyphenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-methoxyphenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-fluorophenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methylphenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3,5-dichlorophenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-naphthyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (4-fluorophenyl) benzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-methoxyphenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5-4-fluorophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-furyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (4-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (3-pyridyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (nitrophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5 - (- 3-methoxyphenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiazole-3-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiazole-3-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N'-dimethylamino) phenyl) thiophene-2-carboxamide);

PL 202 044 B1

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-formiphenyl) thiophene-2-carboxamide) and N- (1-azabicyclo [2.2.2] oct-3-yl) ( 5- (3-hydroxymethyl) phenyl) thiophene-2-carboxamide).

Particularly preferred compounds of the invention include the following: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-pyridyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methoxyphenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-methoxyphenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-fluorophenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methylphenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3,5-dichlorophenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-naphthyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (4-flurophenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-methoxyphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-furyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (4-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (3-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiazole-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiazole-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-formylphenyl) thiophene-2-carboxamide) and (R) -N- (1-azabicyclo [2.2.2 ] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide). Among these compounds mentioned above, the following compounds are particularly preferred: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide) and (R) -N- ( 1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide).

Among the compounds mentioned above, the following compounds are most preferred:

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) -furan-2-carboxamide) and (R) -N- (1-azabicyclo [2.2. 2] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide).

The biaryl carboxamides as defined above are intended for use with a medicament.

The invention also relates to the use of the biaryl carboxamides as defined above for the preparation of a medicament for the treatment or prophylaxis of psychotic disorders and disorders related to intellectual impairment.

The invention also relates to the use of biaryl carboxamides as defined above for the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which activation of the α7 nicotinic receptor in humans is beneficial.

PL 202 044 B1

The invention also relates to the use of the biaryl carboxamides as defined above for the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, disseminated Lewy body dementia, attention deficit hyperactivity disorder, anxiety, schizophrenia , mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders characterized by depletion of cholinergic synapses, Sudden Time Zone Syndrome, smoking cessation disorders, nicotine addiction including addiction to nicotine-containing products, pain or ulcerative colitis.

The invention further relates to a process for the preparation of biarylcarboxamides of general formula I as defined above, consisting of a compound of general formula VI:

₁ in which J represents a halogen atom situated in chest shadow Ar ¹ at a position at which a bond to ring Ar ² is reacted with an organometallic compound of formula VII:

Ar — Μ

VII wherein M is a B (OH) 2 group or an organotin group, in the presence of an organometallic catalyst in the form of a palladium (0) complex and a solvent.

The invention also relates to intermediates of general formula VI:

wherein:

Ar ¹ is a benzene, furan or thiophene ring;

J is halogen, with the proviso that when Ar ¹ is a benzene ring, J may only be a bromine or iodine atom meta or para to the carboxamide group; or their enantiomers and their pharmaceutically acceptable salts.

Preferred compounds of formula VI include the following: N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide);

N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3-iodobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-iodobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3 -carboxamide); and their enantiomers.

Particularly preferred compounds of formula VI are the following compounds:

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide);

(S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromobenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-iodobenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-iodobenzamide);

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and (R) -N- (1-azabicyclo [2.2.2] oct-3- yl) (5-bromothiophene-3-carboxamide).

Unless otherwise indicated, C1-C4-alkyl groups mentioned herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, both alone and part of the other groups may be straight-chain or branched-chain groups, and C3-C4-alkyl groups may also be cyclic groups, i.e. cyclopropyl, cyclobutyl. Alkyl groups mentioned herein may optionally be substituted with 1 to 3 halogen atoms.

Unless otherwise indicated, halogen is fluorine, chlorine, bromine or iodine. The compounds of formula I can be used in the form of pharmaceutically acceptable derivatives, such as solvates and salts. For example, compounds of formula I can form acid addition salts such as conventional pharmaceutically acceptable acids, e.g. maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acid.

Processes for the preparation of the compounds of the invention and the starting and intermediates are described below.

₁

In the reaction schemes and in the description below, A, E, Ar ^1, and Ar ² are as defined above for formula I, unless otherwise indicated.

Compounds of formula I in which E is a single bond can be prepared according to

PL 202 044 B1

The compounds of formula I wherein D represents oxygen and E represents a single bond may also be prepared from compounds of formula VI wherein J represents a halogen or a substituent OSO2CF3 located in the ring Ar ¹ in the position in which the bond is formed from an Ar ² ring by reaction with a suitable organometallic compound of formula VII in the presence of a suitable organometallic catalyst and solvent. Suitable compounds of formula VII include boronic acids in which M is B (OH) 2 and organotin compounds in which M is a suitable trialkylstannyl group, e.g. trimethylstannyl or tri-n-butylstannyl. Suitable organometallic catalysts include palladium (0) complexes, e.g. tetrakis (triphenylphosphine) palladium (0) or a combination of tris (dibenzylideneacetone) dipalladium (0) and a suitable triarylphosphine or triaryl arsine ligand, e.g. triphenylphosphine or tri) (o-phosphine) triphenylarsine. Suitable solvents include inert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or alcohols such as ethanol or mixtures thereof. When the compound of formula VII is boronic acid, the presence of a suitable base in addition to the other reagents is preferred. Suitable bases include sodium carbonate, cesium carbonate, and barium hydroxide. The reaction is carried out at a temperature of 0-120 ° C, and preferably at a temperature of 60-120 ° C.

Compounds of formula I in which D is oxygen and E is a single bond can also be prepared from organometallic compounds of formula VIII by reaction with a compound of formula IX in which J is halogen or OSO2CF3 in the presence of a suitable organometallic catalyst and solvent. Suitable compounds of formula VIII include boronic acids in which M is B (OH) 2 and organotin compounds in which M is a suitable trialkylstannyl group, e.g. trimethylstannyl or tri-n-butylstannyl. Suitable organometallic catalysts include palladium (0) complexes, e.g. tetrakis (triphenylphosphine) palladium (0) or a combination of tris (dibenzylideneacetone) dipalladium (0) and a suitable triarylphosphine or triaryl arsine ligand, e.g. triphenylphosphine or tri) (o-phosphine) triphenylarsine. Suitable solvents include inert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or alcohols such as ethanol or mixtures thereof. When the compound of formula VIII is boronic acid, the presence of a suitable base is preferred in addition to the other reagents. Suitable bases include sodium carbonate, cesium carbonate, and barium hydroxide. The reaction is carried out at a temperature of 0-120 ° C, and preferably at a temperature of 60-120 ° C.

Compounds of formula I where D is oxygen and E is a single bond may also be prepared from compounds of formula X by reaction with a suitable compound of formula XI where L is a suitable leaving group using a suitable acylation procedure . Suitable leaving groups for L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylation procedure is treatment of a compound of formula X with a compound of formula XI at 0-120 ° C in a suitable solvent. It may also be necessary to add a base or, when Y = OH, a coupling agent for the reaction to take place. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when L = OH include: carbodiimides, e.g. 1,3-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride); phosphonium reagents, e.g. benzotriazol-1-yloxytripyrrolidinophosphonium phosphonium or hexafluorophosphate; and uronium reagents, e.g., O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate. , N, N ', N'-tetramethyluronium. Suitable solvents for the reaction are N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or chloroform. The preferred solvent is N, N-dimethylformamide. The reaction is preferably carried out at 0-50 ° C. most preferably at a temperature of 20-30 ° C.

Compounds of formula I in which D is sulfur and E is a single bond can be prepared from compounds of formula I in which D is oxygen and E is a single bond by reaction with a suitable sulfide in a suitable solvent. Preferred sulfides are phosphorus sulfides, especially 4-methoxyphenylthionophosphine sulfide dimer ("Lawesson's reagent"), and diphosphorus pentasulfide. Suitable reaction solvents include aryl hydrocarbon solvents, for example, toluene or xylene. The reaction is carried out at a temperature of 0-200 ° C, and preferably at a temperature of 50-180 ° C.

Certain compounds of formula VI where J is halogen can be prepared from compounds of formula VI where J is hydrogen by reaction with a suitable halogenating agent.

PL 202 044 B1 in a suitable solvent. A suitable halogenating agent is bromine. A suitable solvent is acetic acid. This reaction is preferably carried out at a temperature of 0-50 ° C, and most preferably at a temperature of 0-25 ° C.

Compounds of formula VI where J is OSO2CF3 can be prepared from compounds of formula VI where J is OH by reaction with trifluoromethanesulfonic anhydride or other trifluoromethanesulfonylating agent in the presence of a base and a suitable solvent. Suitable bases include pyridine and 2,6-di-t-butylpyridine. This reaction is preferably carried out at a temperature of -78 to 120 ° C, and most preferably at a temperature of -78 to 0 ° C.

Compounds of formula VI where J is hydrogen, halogen, OH or OSO2CF3 can be prepared from compounds of formula X by reaction with a suitable compound of formula XII where L is a suitable leaving group and J is hydrogen, halogen, OH or OSO2CF3 using an appropriate acylation procedure. Suitable leaving groups for L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylation procedure is treatment of a compound of formula X with a compound of formula XII at 0-120 ° C in a suitable solvent. It may also be necessary to add a base or, when L = OH, a coupling agent for the reaction to take place. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when Y = OH include: carbodiimides, e.g., 1,3-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride); phosphonium reagents, e.g. -1-yloxytripyrrolidinophosphonium; and uronium reagents, e.g., O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate A preferred coupling agent is O-benzotriazol-1-yl-N, N, N, N, N'-tetrafluoroborate. ', N'-tetramethyluronium. Suitable solvents for the reaction are N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or chloroform. The preferred solvent is N, N-dimethylformamide. The reaction is preferably carried out at 0-50 ° C, most preferably at temperature 20-30 ° C.

Compounds of formula VIII in which M is B (OH) 2 may be prepared from compounds of formula VI in which J is hydrogen, halogen or OSO2CF3 according to methods known in the art of chemistry. For example, compounds of formula VI where J is hydrogen or halogen can be converted to compounds of formula VIII where M is B (OH) 2 by conversion to the corresponding aryl lithium or arylmagnesium compounds followed by reaction with trimethyl borate followed by hydrolysis of the obtained borate ester. The reaction is performed in a suitable inert solvent, for example tetrahydrofuran. Alternatively, compounds of formula VI where J is halogen or OSO2CF3 can be converted to compounds of formula VIII where M is B (OH) 2 by reaction with bis (pinacolane) diboron and an organometallic catalyst followed by hydrolysis of the resulting borate ester. Typical procedures used to effect such transformations can be found, e.g., in Organic Syntheses, 1963, Coll. volume. 4, 68; in J. Org. Chem. 1995, 60, 7508.

Compounds of formula VIII in which M is trialkylstannyl can be prepared from compounds of formula VI in which J is hydrogen, halogen or OSO2CF3 using methods known in the art. For example, compounds of formula VI where J is hydrogen or halogen can be converted to compounds of formula VIII where M is trialkylstannyl by conversion to the corresponding aryl lithium or arylmagnesium compounds followed by reaction with the appropriate trialkylstannyl halide. The reaction is carried out in a suitable inert solvent, for example tetrahydrofuran. The reaction is carried out at a temperature of -78 ° C to 20 ° C, preferably at a temperature of -78 ° C to 0 ° C. Alternatively, compounds of formula VI where J is halogen or OSO2CF3 can be converted to compounds of formula VIII where M is trialkylstannyl by reaction with the appropriate bis (trialkyltin). The reaction is carried out in a suitable inert solvent, e.g. tetrahydrofuran, in the presence of a suitable organometallic catalyst, e.g. tetrakis (triphenylphosphine). The reaction is carried out at a temperature of 0 ° C-150 ° C, preferably at a temperature of 20 ° C-100 ° C.

Compounds of formula VIII where M is B (OH) 2 or a trialkylstannyl group can be prepared from compounds of formula X by reaction with a suitable compound of formula XIII where L is a suitable leaving group, M is B (OH) 2 or a trialkylstannyl group using an appropriate acylation procedure. Suitable leaving groups for L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylation procedure is to treat a compound of formula X with a compound of formula XIII at 0-120 ° C at a suitable

In a solvent. It may also be necessary to add a base or, when L = OH, a coupling agent for the reaction to take place. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when L = OH include: carbodiimides, e.g., 1,3-dicyclohexylcarbodiimide hydrochloride or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide; phosphonium reagents, e.g. -1-yl-xytripyrrolidinophosphonium; and uronium reagents, e.g., O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate A preferred coupling agent is O-benzotriazol-1-yl-N, N-yl-N, N'-tetrafluoroborate. , N ', N'-tetramethyluronium. Suitable solvents for the reaction are N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or chloroform. The preferred solvent is N, N-dimethylformamide. The reaction is preferably carried out at 0-50 ° C, most preferably at 0-50 ° C, most preferably while at a temperature of 20-30 ° C.

Compounds of formula XI can be prepared from compounds of formula XII where J is halogen or OSO2CF3, substituents on the Ar ¹ ring at the position where a bond to the Ar ² ring is formed, by reaction with a suitable organometallic compound of formula VII , in the presence of a suitable organometallic catalyst and solvent. Suitable compounds of formula VII are boronic acids, in which M is B (OH) 2, and organotin compounds, in which M is a suitable trialkylstannyl group, e.g. trimethylstannyl or tri-n-butylstannyl. Suitable organometallic catalysts include palladium (0) complexes, e.g. tetrakis (triphenylphosphine) palladium (0) or a combination of tris (dibenzylideneacetone) dipalladium (0) and a suitable triarylphosphine or triaryl arsine ligand, e.g. triphenylphosphine, tri) triphenylarsine. Suitable solvents include inert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or alcohols such as ethanol or mixtures thereof. When the compound of formula VII is boronic acid, the presence of a suitable base is preferred in addition to the other reagents. Suitable bases include sodium carbonate, cesium carbonate, and barium hydroxide. The reaction is carried out at a temperature of 0-120 ° C, and preferably at a temperature of 60-120 ° C.

Compounds of formula XI can also be obtained from organometallic compounds of formula XIII by reaction with a compound of formula IX wherein J is halogen or OSO2CF3 in the presence of a suitable organometallic catalyst and solvent. Suitable compounds of formula XIII include boronic acids, in which M is B (OH) 2, and organotin compounds, in which M is a suitable trialkylstannyl group, e.g. trimethylstannyl or tri-n-butylstannyl. Suitable organometallic catalysts include palladium (0) complexes, e.g. tetrakis (triphenylphosphine) palladium (0) or a combination of tris (dibenzylideneacetone) dipalladium (0) and a suitable triarylphosphine or triaryl arsine ligand, e.g. triphenylphosphine, tri) triphenylarsine. Suitable solvents include inert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, or alcohols such as ethanol or mixtures thereof. When the compound of formula VIII is boronic acid, the presence of a suitable base is preferred in addition to the other reagents. Suitable bases include sodium carbonate, cesium carbonate, and barium hydroxide. The reaction is carried out at a temperature of 0-120 ° C, and preferably at a temperature of 60-120 ° C.

Compounds of formula VII and compounds of formula XIII are either commercially available or can be prepared according to methods known in the art of chemistry. Especially known are methods for converting aryl or heteroaryl halides into aryl or heteroarylboronic acids or aryl or heteroaryltrialkylstannans, methods for converting compounds of formula IX in which J is a halogen atom, into compounds of formula VII and compounds of formula XII, in which J is halogen, to compounds of formula XIII. For example, boronic acids can be synthesized from aryl or heteroaryl halides by conversion to aryl lithium or arylmagnesium compounds followed by reaction with trimethyl borate or by reaction with bis (pinacolate) diboron and an organometallic catalyst followed by hydrolysis of the resulting borane ester (see , e.g., Organic Syntheses, 1963, Coll. Vol. 4, 68; 7. Org. Chem. 1995, 60, 7508). Trialkylstannanes can be synthesized from aryl or heteroaryl halides by conversion to aryl lithium or arylmagnesium compounds followed by reaction with an appropriate chlorotrialkyltin, or by reaction with an appropriate bis (trialkyltin) and an organometallic catalyst.

Compounds of formula I, wherein E is oxygen, sulfur or NR ¹⁰ , can be prepared according to the methods outlined in scheme 2.

PL 202 044 B1

The compounds of formula I wherein D represents oxygen and E represents NR ¹⁰ may be prepared from compounds of formula VI wherein J represents a halogen or OSO2CF3 substituent at the chest shadow of Ar ¹ in the position in which the bond to a nitrogen atom by reaction with an appropriate amine of formula XIV wherein EH is NHR ¹⁰ . This reaction can be carried out by heating in an inert solvent in the presence of a suitable strong base. Suitable inert solvents include ether solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, hydrocarbon solvents, e.g. benzene or toluene, or amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2-pyrrolidinone. A preferred solvent is tetrahydrofuran. Suitable strong bases include alkali metal alkoxides or amine bases, e.g. sodium t-butoxide or potassium t-butoxide, lithium bis (trimethylsilyl) amide, or lithium diisopropylamide. The preferred strong base is sodium t-butoxide. In this reaction, it may be necessary to add an organometallic catalyst, and the reaction is preferably carried out in the presence of such a catalyst. Suitable organometallic catalysts include palladium (0) complexes with suitable phosphine ligands, preferably a triarylphosphine ligand and most preferably a triarylphosphine bidentate ligand. Preferred ligands include 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl or 1,1'-bis (diphenylphosphino) ferrocene. The catalyst can be synthesized by combining a suitable palladium (0) source, e.g. tris (dibenzylideneacetone) dipalladium (0), with a phosphine ligand, and can be prepared either in situ beforehand by adding a palladium source and a phosphine ligand to the reaction mixture. The reaction is carried out at a temperature of 0-150 ° C and preferably at a temperature of 60-120 ° C.

The compounds of formula I wherein D represents oxygen and E represents NR, can also be prepared from compounds of formula IX wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ² in a position in which the bond to atom nitrogen by reaction with the appropriate amine of formula XV wherein EH is NHR ¹⁰ . This reaction can be carried out by heating under neutral

In the presence of a suitable strong base. Suitable inert solvents include ether solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, hydrocarbon solvents, e.g. benzene or toluene, or amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2-pyrrolidinone. A preferred solvent is tetrahydrofuran. Suitable strong bases include alkali metal alkoxides or amine bases, e.g. sodium t-butoxide or potassium t-butoxide, lithium bis (trimethylsilyl) amide, or lithium diisopropylamide. The preferred strong base is sodium t-butoxide. In this reaction, it may be necessary to add an organometallic catalyst, and the reaction is preferably carried out in the presence of such a catalyst. Suitable organometallic catalysts include palladium (0) complexes with suitable phosphine ligands, preferably a triarylphosphine ligand and most preferably a bidentate triarylphosphine ligand. Preferred ligands include 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl or 1,1'-bis (diphenylphosphino) ferrocene. The catalyst can be synthesized by combining a suitable palladium (0) source, e.g. tris (dibenzylideneacetone) dipalladium (0), with a phosphine ligand, and can be prepared either in situ beforehand by adding a palladium source and a phosphine ligand to the reaction mixture. The reaction is carried out at a temperature of 0-150 ° C and preferably at a temperature of 60-120 ° C.

The compounds of formula I wherein D represents oxygen and E represents oxygen or sulfur may be prepared from compounds of formula VI wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ¹ in the position in which the bond an oxygen atom by reaction with an appropriate compound of formula XIV wherein EH is OH or SH. The reaction can be carried out by heating in an inert solvent in the presence of a suitable base. This reaction may require the addition of a catalyst, and preferably the reaction is carried out in the presence of such a catalyst. Suitable inert solvents include ethereal solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2- a pyrrolidinone, or a basic heterocyclic aromatic solvent, e.g. pyridine. The preferred solvent is pyridine. Suitable bases are alkali metal alkoxides and alkali metal carbonates, e.g. potassium carbonate. Suitable organometallic catalysts include copper and its salts, preferably copper (I) salts, most preferably copper (I) iodide. The reaction is carried out at a temperature of 0-150 ° C, and preferably at a temperature of 100-150 ° C.

The compounds of formula I wherein D represents oxygen and E represents oxygen or sulfur may also be prepared from compounds of formula IX wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ² at the position which binds to a nitrogen atom by reaction with the appropriate compound of formula XV in which EH is OH or SH. The reaction can be carried out by heating in an inert solvent in the presence of a suitable base. This reaction may require the addition of a catalyst, and preferably the reaction is carried out in the presence of such a catalyst. Suitable inert solvents include ethereal solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2- a pyrrolidinone, or a basic heterocyclic aromatic solvent, e.g. pyridine. The preferred solvent is pyridine. Suitable bases are alkali metal alkoxides and alkali metal carbonates, e.g. potassium carbonate. Suitable organometallic catalysts include copper and its salts, preferably copper (I) salts, most preferably copper (I) iodide. The reaction is carried out at a temperature of 0-150 ° C, and preferably at a temperature of 100-150 ° C.

Compounds of formula I in which D is oxygen and E is oxygen, sulfur or NR ¹⁰ may also be prepared from compounds of formula X by reaction with a suitable compound of formula XVI in which E is oxygen, sulfur or NR ¹⁰ and L is an appropriate leaving group using an appropriate acylation procedure. Suitable leaving groups for L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylation procedure is treatment of a compound of formula X with a compound of formula XI at 0-120 ° C in a suitable solvent. It may also be necessary to add a base or, when Y = OH, a coupling agent for the reaction to take place. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when L = OH include: carbodiimides, e.g., 1,3-dicyclohexylcarbodiimide hydrochloride or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide; phosphonium reagents, e.g. -1-yloxytripyrrolidine phosphonium; and reagents

Uronium, e.g. O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate. A preferred coupling agent is O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate. Suitable solvents for the reaction include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solvent is N, N-dimethylformamide. This reaction is preferably carried out at a temperature of 0-50 ° C, and most preferably at a temperature of 20-30 ° C.

Compounds of formula XV where EH is OH, SH or NHR ¹⁰ can be prepared from compounds of formula X by reaction with a suitable compound of formula XVII where L is a suitable leaving group and EH is OH, SH or NHR ¹⁰ using an appropriate acylation procedure. Suitable leaving groups for L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylation procedure involves treatment of a compound of formula X with a compound of formula XVII at 0-120 ° C in a suitable solvent. It may also be necessary to add a base or, when L = OH, a coupling agent for the reaction to take place. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when L = OH include: carbodiimides, e.g., 1,3-dicyclohexylcarbodiimide hydrochloride or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide; phosphonium reagents, e.g. -1-yloxytripyrrolidinophosphonium; and uronium reagents, e.g., O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate A preferred coupling agent is O-benzotriazol-1-yl-N, N, N, N, N'-tetrafluoroborate. ', N'-Tetramethyluronium. Suitable solvents for the reaction are N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or chloroform. The preferred solvent is N, N-dimethylformamide. The reaction is preferably carried out at 0-50 ° C, most preferably at temperature 20-30 ° C.

Compounds of formula I, XIV, XV or XVII wherein E is NR ¹⁰ and R ¹⁰ is alkyl can be prepared from compounds of corresponding formulas wherein R ¹⁰ is hydrogen by a suitable alkylation procedure. Typical alkylation procedures include treatment with an appropriate alkyl halide or sulfonate and base, e.g. sodium hydride, in a suitable solvent, e.g. N, N-dimethylformamide, or reductive alkylation using an appropriate aldehyde or ketone together with a suitable reducing agent in the presence of a catalyst acidic and in an inert solvent. The preferred method is reductive alkylation. Suitable reducing agents include sodium borohydride or sodium cyanoborohydride. The preferred reducing agent is sodium borohydride. Suitable inert solvents include water, methanol, or ethanol. The preferred solvent is methanol. Suitable acid catalysts include acetic acid or zinc chloride. A preferred acid catalyst is acetic acid. This reaction is carried out usually at 0-100 ° C and preferably at 20-65 ° C.

Compounds of formula I in which D is sulfur and E is oxygen or NR ¹⁰ can be prepared from compounds of formula I in which D is oxygen and E is oxygen or NR ¹⁰ by reaction with a suitable sulfide in a suitable solvent. Preferred sulfides are phosphorus sulfides, especially 4-methoxyphenylthionophosphine sulfide dimer ("Lawesson's reagent"), and phosphorus pentasulfide. Suitable reaction solvents include aryl hydrocarbon solvents, for example, toluene or xylene. The reaction is carried out at a temperature of 0-200 ° C, and preferably at a temperature of 50-180 ° C.

Compounds of formula XVI wherein D represents oxygen and E represents NR ¹⁰ may be prepared from compounds of formula XII wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ¹ in the position in which the bond to atom nitrogen by reaction with an appropriate amine, a compound of formula XIV wherein EH is NHR ¹⁰ , or alternatively of compounds of formula XVII where EH is NHR ¹⁰ , by reaction with a suitable compound of formula IX wherein J is halogen or OSO2CF3 substituent at the ring Ar ² at a position at which the bond to nitrogen is formed. This reaction can be carried out by heating in an inert solvent in the presence of a suitable strong base. Suitable inert solvents include ether solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, hydrocarbon solvents, e.g. benzene or toluene, or amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2-pyrrolidinone. A preferred solvent is tetrahydrofuran. Suitable strong bases include alkali metal alkoxides or amine bases, e.g. sodium t-butoxide or potassium t-butoxide, lithium bis (trimethylsilyl) amide, or lithium diisopropylamide. The preferred strong base is sodium t-butoxide. A catalyst may need to be added in this reaction

Organometallic and preferably the reaction is carried out in the presence of such a catalyst. Suitable organometallic catalysts include palladium (0) complexes with suitable phosphine ligands, preferably a triarylphosphine ligand and most preferably a bidentate triarylphosphine ligand. Preferred ligands include 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl or 1,1'-bis (diphenylphosphino) ferrocene. The catalyst can be synthesized by combining a suitable palladium (0) source, e.g. tris (dibenzylideneacetone) dipalladium (0), with a phosphine ligand, and can be prepared either in situ beforehand by adding a palladium source and a phosphine ligand to the reaction mixture. The reaction is carried out at a temperature of 0-150 ° C and preferably at a temperature of 60-120 ° C.

Compounds of formula XVI wherein D represents oxygen and E represents an oxygen atom or a sulfur atom, can be prepared from compounds of formula XII wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ¹ in the position in which an oxygen atom or a sulfur atom forms a bond by reaction with a suitable compound of formula XIV wherein EH is OH or SH, or alternatively compounds of formula XVII where EH is OH or SH by reaction with a suitable compound of formula IX. wherein J represents a halogen or OSO2CF3 substituent at the ring Ar ² at a position where an oxygen atom or a sulfur atom forms a bond. The reaction can be carried out by heating in an inert solvent in the presence of a suitable base. This reaction may require the addition of a catalyst, and the reaction is preferably carried out in the presence of such a catalyst. Suitable inert solvents include ethereal solvents, e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether, amide type solvents, e.g. N, N-dimethylformamide or N-methyl-2- a pyrrolidinone, or a basic heterocyclic aromatic solvent, e.g. pyridine. The preferred solvent is pyridine. Suitable bases are alkali metal alkoxides and alkali metal carbonates, e.g. potassium carbonate. Suitable organometallic catalysts include copper and its salts, preferably copper (I) salts, most preferably copper (I) iodide. The reaction is carried out at a temperature of 0-150 ° C, and preferably at a temperature of 100-150 ° C.

Compounds of formula IX, X, and XII, XIV and XVII are either commercially available, known in the literature, or can be prepared according to methods known in the art of chemistry.

It will be appreciated by those skilled in the art that certain aromatic substituents that may be present in the compounds of the invention may be introduced using aromatic substitution reactions, either by functional group transformations to modify existing substituents or by combinations of these pathways. Such reactions may be carried out either before or immediately after the above-described processes and are part of an aspect of the process of the invention. The reagents and reaction conditions for such procedures are known in the art. Examples of specific procedures that can be used include, but are not limited to, introducing electrophilic functional groups into the aromatic ring, e.g., by nitration, halogenation, or acylation; conversion of a nitro group to an amino group, e.g. by reduction such as catalytic hydrogenation; acylation, alkylation, sulfonylation of an amino or hydroxyl group; replacement of an amino group with a different functional group by conversion to an intermediate diazonium salt followed by nucleophilic or free radical displacement of the diazonium salt; or replacement of a halogen atom with another functional group, e.g. by a nucleophilic or organometallic-catalyzed substitution reaction.

If desired, hydroxy, amino or other reactive groups can be protected using protecting groups as described in the literature "Protecting groups in Organic Synthesis", 3rd edition, (1999) by Green and Wuts.

The above-described reactions, unless stated otherwise, are generally carried out at a pressure of about 0.1-0.3MPa, especially at atmospheric pressure (about 0.1MPa).

Unless otherwise stated, the above-described reactions are carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere.

Compounds of the invention and intermediates can be isolated from their reaction mixtures using conventional techniques.

The acid addition salts of the compounds of formula I which may be mentioned include the salts of mineral acids, e.g. hydrochloride or hydrobromide; and organic acid salts such as formate, acetate, maleate, benzoate, tartrate, and fumarate.

Acid addition salts of compounds of formula I can be prepared by reacting the free base or salt, enantiomer or protected derivative thereof with 1 or more equivalents of the appropriate acid. This reaction can be carried out in a solvent or medium in which the salt is

They are insoluble either in a solvent in which the salt is soluble, e.g. water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of these solvents which can be removed in vacuo or by lyophilization. This reaction can be a metathesis reaction or it can be carried out on an ion exchange resin.

Compounds of formula I can exist in tautomeric or enantiomeric forms; all these forms are within the scope of this invention. The various optical isomers can be isolated by resolution of a racemic mixture of the compounds using conventional techniques, e.g., by fractional crystallization or by chiral HPLC. Alternatively, individual enantiomers may be obtained by reacting the corresponding optically active starting compounds under reaction conditions which do not result in racemization.

Compounds of formula VI are useful in the synthesis of compounds of formula I, but their use is not limited to the synthesis of these compounds. For example, the compounds of formula VI are active as ligands of cholinergic receptors and thus have the same utility as described for compounds of formula I.

These compounds also exist in enantiomeric forms and can be used as purified enantiomers, racemates or mixtures.

The pharmaceutical compositions of the invention are intended for the treatment or prevention of a condition or disorder, examples of which are given below, resulting from a dysfunction of the neurotransmission of the nicotinic cholinergic receptor in a mammal, preferably a human. They contain a compound of formula I, an enantiomer or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent such a disorder or condition in admixture with an inert pharmaceutically acceptable diluent or carrier.

For the treatment of the above-mentioned indications, the amount of compound administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered daily at a dose of about 0.1-20 mg per kg body weight of the patient, preferably in divided doses 1-4 times a day or in sustained release form. For humans, the total daily dose is 5-1400 mg, more preferably 10 mg to 100 mg, and unit dosage forms suitable for oral administration contain 2-1400 mg of the compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The compounds of formula I, their enantiomers, and their pharmaceutically acceptable salts, can be used alone or in the form of medicinal preparations suitable for enteral or parenteral administration. The pharmaceutical composition preferably comprises less than 80%, more preferably less than 50% by weight of a compound of the invention in admixture with an inert pharmaceutically acceptable diluent or carrier.

Examples of diluents and carriers are:

- for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose:

- for injection solutions: water, alcohols, glycerin, vegetable oils: for suppositories: natural or hardened oils and waxes.

The pharmaceutical compositions of the invention are typically prepared by admixing the ingredients.

The compounds of the invention, their enantiomers and their pharmaceutically acceptable salts are used in the manufacture of a medicament for the treatment or prophylaxis of one of the diseases or conditions listed below. In the course of treatment or prophylaxis, the patient is administered a therapeutically effective amount of a compound of the invention, an enantiomer or a pharmaceutically acceptable salt thereof.

The compounds of the invention are agonists of nicotinic cholinergic receptors. Without wishing to be bound by theory, it is believed that agonists of the α7 nAChR (nicotinic cholinergic receptor) subtype should be useful in the treatment and prophylaxis of psychotic disorders and intellectual retardation disorders, and that they have advantages over compounds that are or are also agonists of the α4 nAChR receptor. Thus, there are more preferred compounds that are selective for the α7 subtype of the nAChR receptor. The compounds of the invention are indicated as pharmaceuticals, especially in the treatment or prophylaxis of psychotic disorders and disorders related to intellectual impairment. Examples of psychotic disorders include schizophrenia, mania and manic depression, and anxiety. Examples of disorders associated with intellectual disability include Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, dementia in disseminated Lewy body disease, memory loss, and hyperactivity disorder.

PL 202 044 B1 with attention deficit disorder. The compounds of the present invention may also be useful as analgesics in the treatment of pain (including chronic pain) and in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome, and neurodegenerative disorders characterized by a loss of cholinergic synapses. The compounds may furthermore be indicated for the treatment or prophylaxis of Sudden Time Zone Syndrome, for use in promoting smoking cessation, as well as for the treatment or prophylaxis of nicotine addiction (including addiction to nicotine-containing products).

Compounds of the invention are also believed to be useful in the treatment and prophylaxis of ulcerative colitis.

The pharmacological activity of the compounds according to the invention can be determined in the tests given below.

Test A - Affinity test for the α7 nAChR receptor subtype

Binding of 125I-α-bungarotoxin (BTX) to rat hippocampal membranes. Rat hippocampus was homogenized in 20 volumes of cold homogenization buffer (HB: component concentrations (mM): tris (hydroxymethyl) aminomethane 50; MgCl2 1; NaCl 120; KCl 5: pH 7.4). The homogenate was centrifuged for 5 minutes at 1000 g, the supernatant was decanted and the pellet was re-extracted. The combined supernatants were centrifuged for 20 minutes at 12,000 g, washed and resuspended in HB. Membranes (30-80 μg) were incubated with 5 nM [125 I] a-BTX, 1 mg / ml BSA (bovine serum albumin), test drug and 2 mM CaCl ₂ or 0.5 mM EGTA [glycol-bis (e -aminoethyl ether)] for 2 hours at 21 ° C, then filtered and washed 4 times over Whatman glass fiber filters (thickness C) using a Brandel cell harvester. Pre-treatment of the filters for 3 hours with 1% (BSA / 0.01% PEI (polyethyleneimine) in water was significant for the low residual radioactivity of the filters when blank (0.07% total counts per minute). Non-specific binding was described by 100 μM. (-) - nicotine and specific binding was typically 75%.

Test B - Affinity test for the α4 nAChR receptor subtype

[3H] - (-) - nicotine binding. Using a modified procedure from Martino-Barrows and Kellar (Mol Pharm (1987) 31: 169-174), rat brain (cortex and hippocampus) was homogenized as in the [125I] α-BTX binding assay, centrifuged for 20 minutes at 12,000 xg, washed twice and then resuspended in HB containing 100 µM diisopropyl fluorophosphate. After 20 minutes at 4 ° C, membranes (approximately 0.5 mg) were incubated with 3 nM [3H] - (-) - nicotine, test drug, 1 μM atropine, and 2 mM CaCl ₂ or 0.5 mM EGTA for 1 1 hour at 4 ° C followed by filtration over Whatman glass fiber filters (thickness C) (previously treated for 1 hour with 0.5% PEI) using a Brandel cell harvester. Non-specific binding was described by 100 µM carbachol, and specific binding was typically 84%.

Data analysis from binding trials for trials A and B

IC50 values and pseudo-Hill coefficients (nH) were calculated using the ALLFIT nonlinear curve fitting program (DeLean A, Munson P J and Rodbard D (1977) Am. J. Physiol., 235: E97-E102). Saturation curves were fitted to one site model using the ENZFITTER nonlinear regression program (Leatherbarrow, RJ (1987)) and KD values of 1.67 and 1.70 nM were obtained for the 125I-a-BTX and [3H] - (-) ligands, respectively -nicotine. K values were estimated using the general Cheng-Prusoff equation:

Ki = [IC50] / ((2 + ([ligand] / KD]) ⁿ ) ^{1 / n} -1) where the value n = 1 is taken when n _H <1.5, and the value n = 2 is taken when n _H 1.5. Samples were run in triplicate and typically were ± 5%. Ki values were determined using 6 or more drug concentrations. The compounds of the invention are compounds with a binding affinity (Ki) of less than 10 µM in either Test A or B, indicating that the compounds are expected to have useful therapeutic activity.

The compounds of the invention have the advantage of being less toxic, better effective, longer acting, having a wider range of action, stronger action, less side effects and easier absorption, and other useful pharmacological properties.

The general experimental procedures are shown below.

Commercially available reagents were used without further purification. Mass spectra were recorded on a Hewlett Packard 5988A or MicroMass Quattro-1 mass spectrometer, and recorded as m / z for the parent molecule ion. Room temperature means 20-25 ° C.

PL 202 044 B1

Examples

The following examples illustrate preferred embodiments of the invention.

T h e c o n i 1 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide)

Mixture of (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride (655 mg), 5-bromofuran-2-carboxylic acid (681 mg), 1-hydroxybenzotriazole hydrate (457 mg), O-benzotriazole tetrafluoroborate -1-yl-N, N, N ', N'-tetramethyluronium (1.069 g) and N, N-diisopropylethylamine (2.5 ml) in N, N-dimethylformamide (10 ml) were stirred until a homogeneous solution was obtained. then allowed to stand overnight at room temperature. The solution was evaporated and the residue was partitioned between an aqueous sodium hydroxide solution and chloroform. The chloroform layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by chromatography on silica gel using a solid phase extraction cartridge with ammoniacal methanol / chloroform mixtures as eluent. The compound was then dissolved in tetrahydrofuran (20 ml), excess hydrogen chloride (5 ml; 1M diethyl ether solution) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colorless solid (538 mg) by recrystallization from methanol / diethyl ether. ); MS (ES ⁺ ) 299,301 (MH ⁺ ).

T h e d i 2 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide)

A mixture of (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride (4 g), 5-bromothiophene-2-carboxylic acid (4.25 g), 1-hydroxybenzotriazole hydrate (2.77 g), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (6.6 g) and N, N-diisopropylethylamine (14 ml) in N, N-dimethylformamide (100 ml) was stirred at room temperature through the night. The solution was evaporated and the residue was partitioned between an aqueous sodium hydroxide solution and chloroform. The chloroform layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel and eluted with 5% -20% 3.5N methanolic ammonia / chloroform mixtures. Evaporation of the solvent gave a yellow solid (5.87 g); MS (ES ⁺ ) 315,317 (MH ⁺ ).

W i g e d i 3 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide)

A mixture of (S) -N-1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride (1.9 g), 5-bromothiophene-2-carboxylic acid (1.97 g), 1-hydroxybenzotriazole hydrate (1, 28 g), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluorate (3.06 g) and N, N-diisopropylethylamine (8.3 ml) in N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The solution was evaporated and the residue was partitioned between an aqueous sodium hydroxide solution and chloroform. The chloroform layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel and eluted with 5% -20% 3.5M methanolic ammonia / chloroform mixtures. Evaporation of the solvent gave a white solid (3 g); MS (ES ⁺ ) 315,317 (MH ⁺ ).

T h e c o r e d n i 4 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 3-bromobenzoic acid, the compound was purified by chromatography on silica gel with ammoniacal mixtures. methanol / chloroform solution as eluent. The compound was then dissolved in tetrahydrofuran, excess hydrogen chloride (1M solution in diethyl ether) was added and the solution evaporated, then recrystallization from methanol / diethyl ether gave the hydrochloride salt of the title compound as a colorless solid; MS (ES ⁺ ) 309,311 (MH ⁺ ).

T h e r e d n i 5 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4-bromobenzamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 4-bromobenzoic acid, the compound was purified by chromatography on silica gel with ammonia mixtures. methanol / chloroform solution as eluent. The compound was then dissolved in tetrahydrofuran, excess hydrogen chloride (1M solution in diethyl ether) was added and the solution was evaporated, then recrystallized from methanol / t-butyl methyl ether.

The hydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 309,311 (MH ⁺ ).

T h e c o r e n i 6 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-iodobenzamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 3-iodobenzoic acid, the compound was purified by solid phase extraction on silica gel with using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were evaporated, the residue dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colorless solid; MS (ES ⁺ ) 357 (MH ⁺ ).

T h e c o n i 7 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4-iodobenzamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 4-iodobenzoic acid, the compound was purified by solid phase extraction on silica gel with using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were evaporated, the residue dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colorless solid; MS (ES ⁺ ) 357 (MH ⁺ ).

T h e c o r e n i 8 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) (A) 4-Bromothiophene-2-carboxylic acid

Chromium (VI) oxide (20 g) and concentrated sulfuric acid (32 g) were dissolved in water (50 ml), after dissolution, water was added to make a volume of 100 ml. 55 ml of the resulting solution were added dropwise to a stirred solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 ml) at 0 ° C. After 2 hours, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water then extracted with an aqueous sodium hydroxide solution. The alkaline mixture was acidified by the careful addition of concentrated hydrochloric acid solution then extracted with chloroform. The organic layer was then dried (MgSO4), filtered and evaporated. The resulting solid was recrystallized from diethyl ether / hexane to give a colorless solid; MS (ES ⁺ ) 207, 209 (MH ⁺ ).

(B) (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 4-bromothiophene-2-carboxylic acid. The residue from the evaporation of the reaction mixture was partitioned between aqueous hydrochloric acid and chloroform. The aqueous layer was then made basic by the addition of an aqueous sodium hydroxide solution and extracted with chloroform. The organic extracts were dried (MgSO4), filtered and evaporated, then the resulting solid was recrystallized from ethyl acetate / hexane to afford the title compound as a colorless solid: MS (ES ⁺ ) 315, 317 (MH ⁺ ).

N i 9 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3-carboxamide) (A) 5-bromothiophene-3-carboxylic acid

Bromine (46.5 g) in acetic acid (200 ml) was added dropwise to a solution of thiophene-3-carboxylic acid (38 g) in acetic acid (300 ml). After the addition was complete, stirring was continued at room temperature for 30 minutes. The reaction mixture was poured into 2000 ml of an ice / water mixture, and the precipitated solid was filtered and recrystallized from water to obtain a colorless solid; MS (ES ^- ) 205.207 (MH ⁺ ).

PL 202 044 B1 (B) (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3-carboxamide)

The title compound was prepared by a method analogous to that described in the preparation of intermediate 1, from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 5-bromothiophene-3-carboxylic acid. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were evaporated, the residue dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated. After drying in vacuo, the hydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 315,317 (MH ⁺ ).

Example 1 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide)

(R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) hydrochloride (100 mg), phenylboronic acid (45 mg), tetrakis (triphenylphosphine) palladium (0 ) (20 mg), cesium carbonate (547 mg) in a mixture of 1,2-dimethoxyethane (6 ml), ethanol (1.5 ml) and water (1 ml) was stirred for 17 hours while refluxing. condensate under a nitrogen atmosphere. The solution was evaporated and the residue was dissolved in chloroform. The solution was washed with an aqueous sodium carbonate solution and then the organic layer was dried (MgSO4), filtered and evaporated. Purification by HPLC using a gradient of a 1: 1 mixture of ammoniacal methanol in chloroform and chloroform gave the title compound as a colorless solid (63mg); MS (ES ⁺ ) 297 (MH ⁺ ).

Example 2 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-fluorobenzeneboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by filtration through a pad of silica gel to solid phase extraction using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the solvent gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 315 (MH ⁺ ).

Example 3 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3-thiophenboronic acid using palladium tetrakis (triphenylphosphine) ( 0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the solvent gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 313 (MH ⁺ ).

Example 4 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and phenylboronic acid using tetrakis (triphenylphosphine) palladium (0 ) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography on silica gel and eluted with 3% -10% 3.5N methanolic ammonia / chloroform mixtures. Evaporation of the solvent gave the title compound as a colorless solid; MS (ES ⁺ ) 307 (MH ⁺ ).

Example 5 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3-pyridyl) benzamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and pyridine-3-boronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.

The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution was added

(1M solution in diethyl ether) and the solution was evaporated. After drying in vacuo, the dihydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 308 (MH ⁺ ).

Example 6 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and phenylboronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 313 (MH ⁺ ).

Example 7 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3-methoxyphenyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3-methoxyphenylboronic acid using tetrakis (triphenylphosphine ) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 337 (MH ⁺ ).

Example 8 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (2-methoxyphenyl) benzamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 2-methoxyphenylboronic acid using tetrakis ( triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 337 (MH ⁺ ).

Example 9 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3- (N-acetylamino) phenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 364 (MH ⁺ ).

Example 10 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3-fluorophenyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3-fluorobenzeneboronic acid using tetrakis ( triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 325 (MH ⁺ ).

Example 11 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3-methylphenyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3-methylphenylboronic acid using tetrakis ( triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 321 (MH ⁺ ).

PL 202 044 B1

Example 12 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 2-thiophenboronic acid using tetrakis (triphenylphosphine ) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) (MH ⁺ ).

Example 13 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (3,5-dichlorophenyl) benzamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 3,5-dichlorophenylboronic acid using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 375,377 (MH ⁺ ).

Example 14 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (2-naphthyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 2-naphthaleneboronic acid using tetrakis (triphenylphosphine ) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 357 (MH ⁺ ).

Example 15 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3- (4-fluorophenyl) benzamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide) and 4-fluorophenylboronic acid using tetrakis ( triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 325 (MH ⁺ ).

Example 16 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and pyridine-3-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the dihydrochloride of the title compound was obtained as a colorless solid: MS (ES ⁺ ) 298 (MH ⁺ ).

Example 17 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-thiophenboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 303 (MH ⁺ ).

PL 202 044 B1

Example 18 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and benzo [b] furan acid -2-boronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 337 (MH ⁺ ).

Example 19 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and pyridine-4-boronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the dihydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 298 (MH ⁺ ).

Example 20 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 2-thiophenboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 303 (MH ⁺ ).

Example 21 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-methoxyphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 327 (MH ⁺ ).

Example 22 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-methoxyphenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 2-methoxyphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 327 (MH ⁺ ).

Example 23 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 4-fluorophenyl boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 315 (MH ⁺ ).

PL 202 044 B1

Example 24 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 2-naphthaleneboronic acid, using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 347 (MH ⁺ ).

Example 25 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-methylphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 311 (MH ⁺ ).

Example 26 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-furanoboronic acid, using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 287 (MH ⁺ ).

Example 27 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-furyl) furan-2-carboxamide)

A mixture of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) (146 mg),

2- (tri-n-butylstannyl) furan (0.15 ml), tris (dibenzylideneacetone) dipalladium (0) (13 mg), lithium chloride (59 mg) and tri (o-tolyl) phosphine (44 mg) in 1 2-Dimethoxyethane (2 ml) was stirred under reflux under nitrogen for 5 hours. The solution was filtered and evaporated. The compound was purified by filtration through a pad of silica gel to solid phase extraction using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous solution of trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid (59 mg); MS (ES ⁺ ) 287 (MH ⁺ ).

Example 28 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 29 from (R) -N- (1-azabicyclo [2.2.2] -oct-3-yl) (5-bromofuran-2-carboxamide) and 2- (tri- n-butylstannyl) pyridine. The compound was purified by filtration through a pad of silica gel to solid phase extraction using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous solution of trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Evaporation in vacuo gave the dihydrochloride of the title compound as a light yellow solid; MS (ES ⁺ ) 298 (MH ⁺ ).

Example 29 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and pyridine-4-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^®

PL 202 044 B1

C18 with gradient acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 30 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and pyridine-3-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 31 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 27 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 2- (tri-n -butylstannyl) pyridine. The compound was purified by filtration through a pad of silica gel to solid phase extraction using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous solution of trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a light yellow solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 32 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 27 from (R) -N- (1-azabicyclo [2.2.2] -oct-3-yl) (4-bromothiophene-2-carboxamide) and 2- (tri- n-butylstannyl) pyridine. The compound was purified by filtration through a pad of silica gel to solid phase extraction using ammoniated methanol / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous solution of trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the dihydrochloride of the title compound was obtained as a light yellow solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 33 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4- (4-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and pyridine-4-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the dihydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 34 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4- (3-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and pyridine-3-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Fractions

The product containing the product was then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 35 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide) The title compound was prepared analogously to the method described in example 1, from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3- (N-acetylamino) phenylboronic acid, with using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a yellow solid; MS (ES ⁺ ) 354 (MH ⁺ ).

Example 36 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-nitrophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of ethylene glycol dimethyl ether and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a yellow solid; MS (ES ⁺ ) 342 (MH ⁺ ).

Example 37 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-trifluoromethylphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the hydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 365 (MH ⁺ ).

Example 38 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. After drying in vacuo, the hydrochloride of the title compound was obtained as a colorless solid; MS (ES ⁺ ) 331 (MH ⁺ ).

Example 39 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide) The title compound was prepared analogously to the method described in example 1, from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3- (N-acetylamino) phenylboronic acid, with using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 370 (MH ⁺ ).

PL 202 044 B1

Example 40 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorothienyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-fluorophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 331 (MH ⁺ ).

Example 41 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-methoxyphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 343 (MH ⁺ ).

Example 42 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-ethoxyphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 357 (MH ⁺ ).

Example 43 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) furan-2-carboxamide) The title compound was prepared by the method of analogous to the method described in example 1, from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3,5-dimethylisoxazolyl-4-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a colorless solid: MS (ES ⁺ ) 316 (MH ⁺ ).

Example 44 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide) The title compound was prepared by the method of analogous to the method described in example 1, from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3,5-dimethylisoxazolyl-4-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a colorless solid: MS (ES ⁺ ) 332 (MH ⁺ ).

Example 45 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-aminophenylboronic acid hydrochloride, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters column

Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Fractions

The product containing the product was then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid: MS (ES ⁺ ) 328 (MH ⁺ ).

Example 46 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3-carboxamide) and pyridine-3-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and cesium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The product containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M solution in diethyl ether) was added and the solution was evaporated. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 47 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide)

The title compound was prepared in an analogous manner to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and 5- (4-chlorophenyl) furoic acid, the compound was purified by chromatography on silica gel with using ammoniacal methanol / chloroform mixtures as eluent; MS (ES ⁺ ) 331,333 (MH ⁺ ).

Example 48 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiazole-3-carboxamide)

A mixture of (R) -N-1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride (294 mg), 2- (3-pyridyl) thiazole-4-carboxylic acid (304 mg), 1-hydroxybenzotriazole hydrate (199 mg), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (473 g) and N, N-diisopropylethylamine (1.0 ml) in N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solution was evaporated and the residue was partitioned between an aqueous sodium hydroxide solution and chloroform. The solution was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid (428 mg); MS (ES ⁺ ) 315 (MH ⁺ ).

Example 49 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiazole-3-carboxamide)

A mixture of (R) -N-1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride (236 mg), 2- (4-pyridyl) thiazole-4-carboxylic acid (243 mg), 1-hydroxybenzotriazole hydrate (159 mg), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (379 mg) and N, N-diisopropylethylamine (0.82 ml) in N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solution was evaporated and the residue was partitioned between an aqueous sodium hydroxide solution and chloroform. The solution was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid (428 mg); MS (ES ⁺ ) 315 (MH ⁺ ).

Example 50 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) thiophene-2-carboxamide)

To a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide) (92 mg) in 1% acetic acid in methanol (5 ml), formaldehyde (37% solution in water, 0.18 ml) was added. After 30 minutes at room temperature, sodium cyanoborohydride (35 mg) was added and the reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride was made by evaporating the fractions containing the product, dissolving the residue in methanol, adding an excess

Hydrogen chloride solution (1M solution in diethyl ether) and evaporation. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid (54 mg); MS (ES ⁺ ) 356 (MH ⁺ ).

Example 51 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 8-quinolinboronic acid, tetrakis (triphenylphosphine) palladium (0), sodium carbonate in a mixture of DME and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 364 (MH ⁺ ).

Example 52 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and pyridine-3-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 53 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and pyridine-4-boronic acid , using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 54 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide)

The title compound was prepared in an analogous manner to that described in Example 27 from (S) -N- (1-azabicyclo [2.2.2] -oct-3-yl) (5-bromothiophene-2-carboxamide) and 2- (tri- n-butylstannyl) pyridine. The compound was purified by flash chromatography using 5% -20% 3.5N ammoniacal methanol / chloroform as eluent. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 314 (MH ⁺ ).

Example 55 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and phenylboronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 313 (MH ⁺ ).

PL 202 044 B1

Example 56 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3-carboxamide) and phenylboronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. Evaporation of the product-containing fractions gave the trifluoroacetate salt of the title compound as a colorless solid; MS (ES ⁺ ) 313 (MH ⁺ ).

Example 57 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and phenylboronic acid using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. CONCERNING relationship was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from ethyl acetate gave the hydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 313 (MH ⁺ ).

Example 58 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-cyanophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a colorless solid; MS (ES ⁺ ) 338 (MH ⁺ ).

Example 59 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide)

Sodium methoxide was added to a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide) (550 mg) in methanol (5 ml) (14 mL, 0.5M solution in methanol) followed by paraformaldehyde (117 mg). The mixture was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, sodium borohydride (175 mg) was added, and the solution was heated under reflux for 2 hours. Aqueous potassium hydroxide (1M, 1.4 ml) was added. Heating under reflux was performed for 2 hours, then the reaction mixture was left at room temperature for 16 hours. The solvent was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was made by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a colorless solid (120 mg); MS (ES ⁺ ) 342 (MH ⁺ ).

Example 60 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide)

To (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide) (900 mg) was added 48% aqueous hydrobromic acid (10 ml ) and glacial acetic acid (10 ml). After refluxing for 4 hours, saturated aqueous sodium carbonate and solid sodium carbonate were added to adjust to pH = 10. The aqueous layer was extracted with chloroform and the combined extracts were dried over magnesium sulfate. After filtration and evaporation, the residue was purified by flash chromatography using 5% -20% 3.5M methanolic ammonia / chloroform mixtures as

The eluent. The resulting product was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the hydrochloride of the title compound as a colorless solid (32 mg); MS (ES ⁺ ) 329 (MH ⁺ ).

Example 61 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide)

A mixture of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) (315 mg),

3-aminopyridine (188 mg), tris (dibenzylideneacetone) dipalladium (0) (46 mg), racemic 2,2'-bis (diphenylphosphino) -1,1-binaphthyl (62 mg) and sodium tert-butoxide (192 mg) in tetrahydrofuran (10 mL) was refluxed for 20 hours. The mixture was filtered and the residue was purified by flash chromatography using 5% -20% 3.5M methanolic ammonia / chloroform mixtures as eluent. The compound was further purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride of the title compound as a yellow solid (77 mg); MS (ES ⁺ ) 329 (MH ⁺ ).

Example 62 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography with gradient elution of 5% -20% 3.5M methanolic ammonia / chloroform mixtures to afford the title compound as a colorless solid; MS (ES ⁺ ) 347 (MH ⁺ ).

Example 63 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide) A mixture of (R) - N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide) (0.98 g), morpholine (0.5 ml), tris (dibenzylideneacetone) dipalladium (0) (132 mg), racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (180 mg) and sodium tert-butoxide (554 mg) in tetrahydrofuran (25 ml) was heated to reflux. reflux for 20 hours under a nitrogen atmosphere. The mixture was filtered and the residue was purified by flash chromatography eluting with a gradient of 5% -20% 3.5M methanolic ammonia / chloroform mixtures. The mixture was then subjected to reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The hydrochloride salt was made by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride salt of the title compound as a solid (400 mg); MS (ES ⁺ ) 398 (MH ⁺ ).

Example 64 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide)

To a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide) (311 mg) in methanol and acetic acid (1: 1 10 ml), a catalytic amount of 10% Pd-C was added and the mixture was hydrogenated at 0.34MPa for 36 hours. The mixture was filtered through a celite pad. The residue was purified first by flash chromatography using 5-20% 3.5M methanolic ammonia / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid . The free base was prepared by basifying the product fractions and extracting with chloroform followed by evaporation to give the title compound (23 mg); MS (ES ⁺ ) 342 (MH ⁺ ).

PL 202 044 B1

Example 65 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide)

To a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) (463 mg) in pyridine (10 ml) was added phenol (158 mg), iodide copper (32 mg) and potassium carbonate (97 mg). The mixture was stirred at 125 ° C for 65 hours under nitrogen atmosphere. Water was added and the aqueous layer was extracted with chloroform. After evaporation the residue was purified by flash chromatography using 5-20% 3.5M methanolic ammonia / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous solution of trifluoroacetic acid. The free base was prepared by basifying the product fractions and extracting with chloroform followed by evaporation to give the title compound (80mg); MS (ES ⁺ ) 329 (MH ⁺ ).

Example 66 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide) and 3-aminophenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using 5-20% 3.5M methanolic ammonia / chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The free base was prepared by basifying the product fractions and extracting with chloroform followed by evaporation to give the title compound; MS (ES ⁺ ) 312 (MH ⁺ ).

Example 67 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide)

To a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide) (220 mg) in 1% acetic acid in ethanol (10 ml), formaldehyde (0.26 ml) was added. After 45 minutes, sodium cyanoborohydride (89 mg) was added. The mixture was stirred for 4 hours. Water was added and the solution was made basic to pH> 10 by adding solid sodium carbonate. The aqueous layer was extracted with chloroform and the extracts dried over magnesium sulfate, filtered and evaporated. The compound was purified by flash chromatography using 5-20% 3.5M methanolic ammonia / chloroform mixtures as eluent. The hydrochloride salt was prepared by evaporating the fractions containing the product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1M solution in diethyl ether) and evaporating. Recrystallization from methanol / diethyl ether gave the dihydrochloride salt of the title compound as a solid (141 mg); MS (ES ⁺ ) 340 (MH ⁺ ).

Example 68 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3-formylphenyl) thiophene-2-carboxamide)

The title compound was prepared by a method analogous to that described in Example 1 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide) and 3-formylphenylboronic acid, using tetrakis (triphenylphosphine) palladium (0) and sodium carbonate, in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak ^® C18 eluting with a gradient of acetonitrile / 0.1% aqueous trifluoroacetic acid. The free base was prepared by basifying the fractions containing the product. The aqueous layer was extracted with chloroform and evaporated to give the title compound; MS (ES ⁺ ) 341 (MH +).

Example 69 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide)

Sodium borohydride was added to a solution of (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-formylphenyl) thiophene-2-carboxamide) (875 mg) in methanol (15 ml) (97.2 mg). The mixture was then stirred at room temperature for 4 hours. The residue was partitioned between water and chloroform. The extracts were dried over magnesium sulfate, filtered and evaporated, then the residue was purified by flash chromatography using 5-20% 3.5M methanolic ammonia / chloroform mixtures as eluent to afford the title compound (547mg); MS (ES ⁺ ) 343 (MH ⁺ ).

Claims (26)

1. Biaryl carboxamides of general formula I: D where: A means: E is a single bond, oxygen, sulfur or NR ¹⁰ ; R is hydrogen or methyl; Ar ¹ is a benzene, furan, thiophene or thiazole ring; Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl; Ar ¹ and Ar ² are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO 2, NR ¹ R ^2, CH 2 NR ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3; but when Ar ¹ is a benzene ring and Ar ² is quinolinyl then Ar ² is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ^2, CH 2 NR ¹ R ^2, OR ^3, CH 2 OR ³ and CO 2 R ^4; R ¹ , R ² and R ³ are independently C 1 -C 4 -alkyl, C (O) R ⁵ , C (O) NHR ⁶ , C (O) R ⁷ , SO ² R 8, or R ¹ and R ² together can be ( CH2) JG (CH2)] k where G is oxygen, sulfur, NR ⁹ or a single bond; j is 2, 3 or 4; k is 0, 1 or 2; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently C1-C4-alkyl; or their enantiomers and their pharmaceutically acceptable salts, except that formula I does not represent: 2. Compounds according to claim 1 Wherein D is oxygen. 3. Compounds according to claim 1 2, wherein E is a single bond. 10 4. The compound of claim 1 Wherein E is oxygen or NR ¹⁰ . Compounds according to claim 1 1 where A is PL 202 044 B1 6. Compounds according to claim 1 5, wherein Ar ² is phenyl, furyl, thiophenyl or pyridyl. ₁ 7. Compounds according to claim The compound of claim 1, wherein Ar ¹ is substituted with only a carboxamide group or a C (= D) NHA thiocarboxamide group. 8. Compounds according to claim 1 The compound of claim 7, wherein -EAr ² and the C (= D) NHA carboxamide or thiocarboxamide group, the Ar ¹ ring substituents, are in the 1.3 position with respect to each other. 9. Compounds according to claims 1 wherein Ar ¹ or Ar ² is optionally substituted with a substituent selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO 2, NR ¹ R ^2, CH 2 NR ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3. 10. Compounds according to claim 1 1, in which: A means: D is oxygen; E is a single bond; Ar ¹ is a benzene, furan, thiophene or thiazole ring; Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl; the aromatic ring of Ar ¹ is substituted with only Ar ² and a carboxamide group, C (= O) NHA; Ar ² is optionally substituted with a substituent selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ² , CH2N R ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3. 11. Compounds according to claim 1 The compounds of claim 10, wherein Ar ¹ is a benzene, furan or thiophene ring, or enantiomers thereof, and pharmaceutically acceptable salts thereof. 12. Compounds according to claim 1 1, where A stands for: D is oxygen; E is oxygen or NH; Ar ¹ is a benzene, furan, thiophene or thiazole ring; Ar ² is phenyl, furyl, thiophenyl, pyridyl, naphthyl, benzofuranyl, or quinolinyl; the aromatic ring Ar ¹ is substituted solely with EAr ² and the group C (= O) NHA; Ar ² is optionally substituted with a substituent selected from the group consisting of halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, CN, NO2, NR ¹ R ² , CH2NR ¹ R ² , OR ³ , CH2OR ³ , CO2R ⁴ and CF3. 13. Compounds according to claim 1 12, wherein Ar ¹ represents a benzene ring, furan or thiophene, or the enantiomers and pharmaceutically acceptable salts thereof. 14. Compounds according to claim 1 13, wherein the EAR ² and the carboxamide group, C (= O) NHA, and in _one ścieniu ring Ar ¹ are in the 1,3 positions relative to each other, or the enantiomers and pharmaceutically acceptable salts thereof. 15. The compound of claim 1 1, which is a compound selected from the group consisting of: N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-pyridyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methoxyphenyl) benzamide); PL 202 044 B1 N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-methoxyphenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-fluorophenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methylphenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3,5-dichlorophenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-naphthyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (4-fluorophenyl) benzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-methoxyphenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-4-fluorophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-furyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (4-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (3-pyridyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (nitrophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5 - (- 3-methoxyphenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiazole-3-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiazole-3-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N'-dimethylamino) phenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide); PL 202 044 B1 N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-formylphenyl) thiophene-2-carboxamide) and N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxymethyl) phenyl) thiophene-2-carboxamide). 16. The compound of claim 1 1, which is a compound selected from the group consisting of: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-pyridyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methoxyphenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-methoxyphenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-fluorophenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-methylphenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3,5-dichlorophenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-naphthyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (4-flurophenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-methoxyphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-furyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (4-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (3-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiazole-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiazole-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-formylphenyl) thiophene-2-carboxamide) and (R) -N- (1-azabicyclo [2.2.2 ] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide). 17. The compound of claim 1 1, which is a compound selected from the group consisting of: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylfuran-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3-thienyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-phenylbenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (3- (N-acetylamino) phenyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3- (2-thienyl) benzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-thienyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-benzo [b] furanyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-thienyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-naphthyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methylphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-furyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4- (2-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-ethoxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3,5-dimethylisoxazol-4-yl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-chlorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (8-quinolinyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenylthiophene-3-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-methylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridylamino) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (4-morpholinyl) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (aminomethyl) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N, N-dimethylamino) phenyl) furan-2-carboxamide) and (R) -N- ( 1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide). 18. The compound of claim 1 1, which is a compound selected from the group consisting of: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-methoxyphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-fluorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (4-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-nitrophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-trifluoromethylphenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-chlorophenyl) furan-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3- (N-acetylamino) phenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-3-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-pyridyl) thiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (2-pyridyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-phenylthiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-cyanophenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-hydroxyphenyl) thiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-phenoxythiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5- (3-aminophenyl) -furan-2-carboxamide) and (R) -N- (1-azabicyclo [2.2. 2] oct-3-yl) (5- (3- (hydroxymethyl) phenyl) thiophene-2-carboxamide). 19. The biaryl carboxamides as defined in claim 1 1-18 for use as a medicament. 20. The use of biaryl carboxamides as defined in claim 1 1-18 for the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders and disorders related to intellectual retardation. 21. The use of biaryl carboxamides as defined in claim 1 For the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which activation of the α7 nicotinic receptor in humans is beneficial. 22. Use of the biaryl carboxamides as defined in claim 1 1-18 for the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, disseminated Lewy body dementia, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania or depression mania, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders characterized by a depletion of cholinergic synapses, Sudden Time Zone Syndrome, smoking cessation disorders, nicotine addiction including addiction to nicotine products, pain or ulcerative colitis. PL 202 044 B1 23. A process for the preparation of biaryl carboxamides of general formula I as defined in claim 1 3. The method of claim 1, wherein the compound of general formula VI: 18, in which J is a halogen atom in the ring Ar ¹ in the position where a bond with the ring Ar ² is formed, is reacted with an organometallic compound of general formula VII: Ar — Μ VII wherein M is a B (OH) 2 group or an organotin group in the presence of an organometallic catalyst in the form of a palladium (0) complex and a solvent. 24. Intermediates of general formula VI: wherein: Ar ¹ is a benzene, furan or thiophene ring; J is halogen, with the proviso that when Ar ¹ is a benzene ring, J may only be a bromine or iodine atom meta or para to the carboxamide group; or their enantiomers and their pharmaceutically acceptable salts. 25. The compound of claim 1 24, which is a compound selected from the group consisting of: N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (3-iodobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-iodobenzamide); N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-3-carboxamide); and their enantiomers. 26. The compound of claim 1 24, which is a compound selected from the group consisting of: (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromofuran-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide); (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) (5-bromothiophene-2-carboxamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-bromobenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromobenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (3-iodobenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-iodobenzamide); (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) (4-bromothiophene-2-carboxamide) and (R) -N- (1-azabicyclo [2.2.2] oct-3- yl) (5-bromothiophene-3-carboxamide).